Exametazime (formula I) is a propylene amine oxime ligand, which is used for the preparation of lipophilic technetium-99m (Tc-99m) complex. This complex is used as diagnostic aid (radioactive imaging agent) as an adjunct in the detection of altered regional cerebral perfusion in stroke and localization of intra-abdominal infection and inflammatory bowel disease.

The complex is marketed by GE Healthcare under brand name Ceretec® kit, which is having strength of 0.5 mg exametazime per vial as injectable.
Exametazime is chemically known as (SS,RR)-4,8-diaza-3,6,6,9-tetramethyl undecane-2,10-dione bisoxime, formerly it was also known as hexamethylpropylene amine oxime (HMPAO). Exametazime is a racemic mixture of d′ (formula Ia) and ‘l’ (formula Ib) enantiomers. Exametazime and its lipophilic complex with technetium-99m (Tc-99m) are specifically covered in expired U.S. Pat. No. 4,789,736, assigned to Amersham International PLC.
U.S. Pat. No. 4,789,736 discloses preparation of exametazime (Scheme 1), which involves reaction of 2,3-butanedione monoxime (formula II) with 2,2-dimethyl-1,3-propanediamine (formula III) in benzene, in presence of acetic acid to afford diimine derivative 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime (formula IV). Benzene is known to be carcinogenic and is not used as solvent, as per the current norms. The diimine derivative is reduced with sodium borohydride in aqueous ethanol followed by double recrystallization from acetonitrile to afford pure product, which is a mixture of ‘d’, ‘l’ and meso isomers. U.S. Pat. No. 4,789,736 further discloses methods for separation of meso and d, l-isomers either by normal-phase HPLC or by fractional crystallisation. Fractional crystallization method involves double recrystallization of crude product from acetonitrile to afford dl-enriched material, which is further subjected to slow recrystallization from ethyl acetate to afford enantiomerically pure dl isomer i.e. exametazime, as large clear crystals.

U.S. Pat. No. 4,789,736 reported 0.8˜0.9% of exametazime (formula I) yield from a mixture of ‘l’ and meso isomers via fractional recrystallization.
CS276287B6 assigned to Ustav Jaderneho Vyzkumu, discloses preparation of exametazime (Scheme 2), the process involves reaction of 2,3-butanedione monoxime (formula II) with 2,2-dimethyl-1,3-propanediamine (formula III) in benzene, in presence of weak acid cation Amberlite IRC-50 catalyst to afford diimine derivative 4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime (formula IV). Benzene is known to be carcinogenic and is not used as solvent, as per the current norms. The diimine derivative is reduced with sodium borohydride in aqueous ethanol to afford crystals of ‘d’, ‘l’ and meso isomers. These crystals are recrystallized three times with ethyl acetate to give undesired pure meso form. The filtrate of reduction step is diluted with water and extracted with chloroform. The extracts are evaporated and further recrystallized five times from ethyl acetate to afford exametazime.
The said process involves multiple recrystallizations, which in turn reduces the overall yield of exametazime.

KR134565B1 assigned to Korea Inst. Sci. & Tech., discloses reductive amination method which involves reaction of 2,3-butanedione monoxime (formula II) with 2,2-dimethyl-1,3-propanediamine (formula III) in anhydrous methanol, in presence of sodium cyano borohydride to afford a mixture of ‘d’, ‘l’ and meso isomers. This mixture is recrystallized in ethyl acetate to afford exametazime (Scheme 3). However, the patent is silent about the enantiomeric purity of exametazime.

KR615893B1 and its divisional patent KR632963B1 assigned to Dong A Pharm. Co. Ltd., discloses a method for the preparation of exametazime (Scheme 4) by avoiding the fractional crystallization step, the process involves condensation of dimethyl malonic acid with L-alanine methyl ester hydrochloride and D-alanine methyl ester hydrochloride to get corresponding stereoisomers, separately. Mixing equivalent moles of these stereoisomers and further reducing them to afford racemic mixture of amino alcohol intermediate. Protecting the nitrogen of amino alcohol intermediate followed by oxidation and Grignard reaction affords secondary alcohol intermediate, which on oxidation followed by condensation with hydroxylamine affords racemic mixture of nitrogen protected dioxime derivative. Deprotection of nitrogen affords exametazime.

The process involves multiple steps, which in turn reduces the overall yield of exametazime. Chemical & Pharmaceutical Bulletin, Volume: 48, Issue: 2, Pages: 288-289, 2000, discloses one-pot procedure for the preparation of exametazime. The process involves reaction of 2,3-butanedione monoxime (formula II) with 2,2-dimethyl-1,3-propanediamine (formula III) in ethanol, followed by reduction with sodium borohydride to afford a mixture of ‘d’, ‘l’ and meso isomers. The said article discloses single recrystallization in ethyl acetate to afford a mixture of (70:30) dl and meso isomers. The known processes for the preparation of exametazime are not cost effective due to multiple recrystallizations, which is required for the removal of unwanted meso isomer from the racemic mixture of d and l isomers. The multiple recrystallizations reduce the overall yield of exametazime. The known processes also use benzene as solvent, which is carcinogenic.
Thus, there is a need to develop an alternative and improved process for the preparation of exametazime, which is simple, environment friendly, cost effective and improves the overall yield along with enantiomeric purity of exametazime.